(1) Field of the Invention
The present invention relates to a process for producing a cyano ring-substituted arene or heteroarene borane which comprises reacting a ring-substituted cyano arene or heteroarene with an HB or B—B organic compound in the presence of a catalytically effective amount of an iridium complex with three or more substituents, excluding hydrogen, bonded to the iridium and an organic ligand, which is at least in part bonded to the iridium, to form the ring-substituted cyano substituted arene or heteroarene borane.
(2) Description of Related Art
Alkyl and arylboronic esters and acids are versatile alkyl and aryl transfer reagents in organic chemistry wherein the boron serves as a “mask” for a broad range of heteroatoms and functional groups. Some of the most remarkable and broadly used applications of organoboron chemistry are catalytic cross-coupling reactions of C—B and C—X (X═Cl, Br, or I) groups which yield new C—C bonds as shown below.
In the pharmaceutical industry, organoboron complexes are key building blocks for drug manufacturing, versatile reagents for high-throughput parallel synthesis in drug discovery, and exhibit some useful and unique biological activities.
Arylboronate esters and the corresponding acids are presently prepared by reacting Grignard reagents generated from halogenated aromatics and magnesium metal with alkyl borate reagents. A related method involves the reaction of alkyllithium reagents with aromatic halides or arenas to generate lithium reagents which are subsequently reacted with alkyl borates. Moreover, introduction of the Bpin group using other methods, such as Miyaura's cross-coupling reactions of alkoxydiboron reagents and aryl halides, are inconvenient because access to the 2-halogenated compounds is extremely limited (Ishiyama, T. et al., J. Org. Chem. 1995, 60, 7508-7510). Significant limitations of the current technologies include: (1) the reactions are run typically in ethereal solvents, (2) halogenated aromatics must be synthesized from hydrocarbon feedstocks, (3) for large-scale synthesis, unreacted chlorinated aromatic starting materials and biaryl byproducts can create significant environmental hazards and pose waste disposal problems, (4) in some instances attempted product isolation has resulted in explosions attributed to unreacted lithium and magnesium intermediates, (5) Grignard and organolithium reagents can be incompatible with a range of common functional groups including esters, amides, bromides, chlorides, iodides, alcohols, acids, and the like, and (6) cryogenic cooling is sometimes required to prevent side reactions.
Aromatic hydrocarbons are fundamental chemical building blocks, and their reactivity is a cornerstone of organic chemistry. Their utility derives largely from the regiochemical fidelity embodied in electrophilic aromatic substitutions (Taylor, R., Electrophilic Aromatic Substitution; John Wiley and Sons: New York, 1990). While steric effects can influence electrophilic aromatic substitution, electronic effects typically dominate. For electrophilic aromatic substitution (EAS) reactions, substituents on aromatic rings fall into two classes: ortho, para directors and meta directors. When directing groups are positioned to work in concert, regioselectivity can be complete as in the classic example of nitration at the 3-postion of 4-bromobenzonitrile (Scheme 1, electronically preferred product, FG=NO2) (Schopff, M., Ber. 1890, 23, 3435-3440). For most disubstituted benzenes, EAS does not usually offer well-defined regiochemical outcomes. For example, two of the three possible arrangements of directing groups in 1,4-substituted benzenes give poor regioselectivity as shown in Scheme 1.
For the functionalization at positions meta to ortho, para directors and/or ortho to meta directors, alternate methods to electrophilic aromatic substitutions are required. In the case of certain meta directing substituents, directed ortho metalation (DoM) constitutes a powerful method for functionalization at the adjacent positions, provided that the substituent is a sufficiently strong directed metalation group (DMG) (Whisler, M. C., MacNeil, S.; Snieckus, V.; Beak, P., Angew. Chem. Int. Edit. 2004, 43, 2206-2225). For disubstituted benzenes, the regioselectivity of DoM depends on the positions of the substituents and their ranking in the DMG hierarchy. 1,3-Subsituted benzenes can often be derivatized selectively at the 2-position because DMG's can act in concert to direct metalation.
In contrast, DMG's can compete in 1,2- and 1,4-substituted benzenes. Therefore high regioselectivities are typically realized when there is a substantial difference in relative DMG powers. For example, while DoM protocols can be effective for functionalizing ortho to cyano groups in simple aromatic nitriles,(Kristensen, J.; Lysen, M., Vedso, P., Begtrup, M., Org. Lett. 2001, 3, 1435-1437; (b) Pletnev, A. A.; Tian, Q. O., Larock, R. C., J. Org. Chem. 2002, 67, 9276-9287) the presence of other groups can subvert the selectivity. Sometimes the regiochemical outcome is unexpected. For instance, competitive 2,5-dilithiation of 4-bromobenzonitrile occurs with LDA (Lulinski, S., Serwatowski, J., J. Org. Chem. 2003, 68, 9384-9388) and deprotonation at the 3-position has been reported with the hindered phosphazene base, P4-t-Bu, (Imahori, T., Kondo, Y., J. Am. Chem. Soc. 2003, 125, 8082-8083) even though the DMG ranking of CN is greater than Br. In fact, there are no documented transformations of 4-bromobenzonitrile that are selective for the 2-position. Moreover, examples of functionalization at the 2-position in other 4-substituted benzonitriles are limited, and there are no general approaches toward this end (Wang, C et al., J. Org. Chem. 1998, 63, 9956-9959; Kim, B. H., et al. J. Chem. Soc.-Perkin Trans. 1 2001, 2035-2039; and Sonoda, M., S., Bull. Chem. Soc. Jpn. 1997, 70, 3117-3128). This is unfortunate because aryl nitrites have a rich chemistry, and are particularly useful entries into heterocyclic systems (Meyers, A. I., et al., The Chemistry of the Cyano Group. In the Chemistry of the Functional Groups; Patai, S. et al., Eds. Wiley & Sons: New York, 1970; Chapter 8; Fatiadi, A. J., In Supplement C: The Chemistry of the Triple-bonded Functional Groups; Patai, S., et al Eds. Wiley & Sons: New York, 1983; Chapter 26).
An alternate strategy for functionalizing benzonitriles that can potentially complement electrophilic aromatic substitutions and DoM's is to differentiate positions based on steric effects (Scheme 1). Since the first report by Ittel and co-workers in 1976, (Ittel, S. D. et al., J. Am. Chem. Soc. 1976, 98, 6073-6075) there have been several reports of transition metal mediated C—H activations where steric, not electronic, effects are the overriding factors in regioselection. More recently, significant progress has been made in coupling C—H activation with subsequent transformations of the nascent M-C bond to design new catalytic processes (Goldberg, K. I. et al., Activation and Functionalization of C—H Bonds. American Chemical Society: Washington, D.C. 2004). Since 1999, we,(Iverson, C. N., et al., J. Am. Chem. Soc. 1999, 121, 7696-7697; Cho, J.-Y et al., J. Am. Chem. Soc. 2000, 122, 12868-12869; Cho, J. Y., et al Science 2002, 295, 305-308; Maleczka, R. E., Jr. et al, J. Am. Chem. Soc. 2003, 125, 7792-7793; Chotana, G. A. et al., J. Am. Chem. Soc. 2005, 127, 10539-10544; Tse, M. K. et al., Org. Lett. 2001, 3, 2831-2833; Holmes, D. et al., Org. Lett. 2006, 8, 1407-1410; and Shi, F. et al., Org. Lett. 2006, 8, 1411-1414); and others, (Ishiyama, T. et al., J. Am. Chem. Soc. 2002, 124, 390-391; Ishiyama, T. et al., Angew. Chem. Int. Edit. 2002, 41, 3056-3058; Takagi, J et al., Tetrahedron Lett. 2002, 43, 5649-5651; Ishiyama, T. et al., Chem. Commun. 2003, 2924-2925; Ishiyama, T. et al., Adv. Synth. Catal. 2003, 345, 1103-1106; and Mertins, K. et al., J. Mol. Catal. A: Chem. 2004, 207, 21-25) have been particularly interested in utilizing Ir-catalyzed borylations of arenes to tap the unique regioselectivities available to sterically directed C—H activations.
In light of the above limitations of the current processes for producing cyano substituted arene boronate esters and acids, there remains a need for a synthetic route to synthesizing boronate esters and acids that does not have the limitations of the current processes.
Objects
It is an object of the present invention to provide a process for synthesizing cyano substituted arene or heteroarene boranes. A further object of the present invention is to provide a process for synthesizing ring-substituted cyano boranes by metal catalyzed activations of C—H bonds in arenes or heteroarenes and B—H or B—B bonds in boron reagents to produce novel B—C bonds. These and other objects of the present invention will become increasingly apparent with reference to the following drawings and preferred embodiments.